Abstract PD2-08: Gene expression analysis and association with treatment response in postmenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer in the MONALEESA-3 study
Notice bibliographique
Résumé
Abstract Background: In the Phase III MONALEESA-3 study (NCT02422615),the cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib(RIB) + fulvestrant significantly prolonged progression-free survival (PFS) vs placebo (PBO) + fulvestrant in postmenopausal patients (pts) with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC; median, 20.5 vs 12.8 mo; hazard ratio 0.593 [95% CI, 0.480-0.732]; P< .001; Slamon D et al. J Clin Oncol. 2018). Previous MONALEESA-3 biomarker analyses, including those based on immunohistochemistry and next-generation sequencing of baseline circulating tumor DNA (ctDNA), showed consistent PFS benefit with ribociclib (Neven P et al. ESMO 2018; Neven P et al. SABCS 2018). We present analyses of gene expression in baseline tumor samples from the MONALEESA-3 trial and potential correlations with PFS. Methods: Postmenopausal pts with ≤1 prior line of ET for advanced disease were enrolled and randomized 2:1to receive either RIB or PBO plus fulvestrant. Gene expression data were generated for 531 patients using tumor samples collected before treatment using the NanoString 800-gene nCounter® GX Customized Panel. Correlations between PFS and mRNA expression levels were assessed for various genes, including those relevant to breast cancer, the CDK4/6 pathway, the mitogen-activated protein kinase (MAPK) pathway, receptor tyrosine kinases (RTKs), estrogen receptor (ER) signaling and response to estrogen, and proliferation; specific genes are listed in the Table. Pts were classified into low and high mRNA expression subgroups, with median values of gene expression levels or pathway scores as the cutoff. The Kaplan-Meier method was used to calculate median PFS with 95% CIs in each treatment arm by biomarker subgroup. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs. Results: PFS hazard ratios for all biomarker subgroups favored RIB + fulvestrant vs PBO + fulvestrant (Table). There appeared to be a trend toward greater PFS benefit with RIB in patients with lower expression of BCL2 or genes involved in ER signaling. Similar RIB PFS benefit was observed regardless of the expression level of the CCNE1 gene, RTK genes, genes involved in tumor cell proliferation, CDK4/6 pathway genes, or MAPK pathway genes. Conclusions: The PFS benefit observed with RIB vs PBO across gene expression subgroups in this analysis was generally consistent with that seen in the primary analysis of MONALEESA-3. Table. Progression-Free Survival by Gene Expression SubgroupGene/PathwayLow ExpressionHigh ExpressionPBORIBPBORIBCCNE1an9017682183Median PFS, mo14.5220.0412.7816.62HR (95% CI)0.62 (0.44-0.87)0.66 (0.46-0.94)BCL2an7918793172Median PFS, mo9.4317.9418.4620.04HR (95% CI)0.47 (0.33-0.66)0.8 (0.55-1.14)Proliferationbn9017682183Median PFS, mo12.6819.0912.9120.04HR (95% CI)0.58 (0.41-0.81)0.72 (0.5-1.03)ER signalingcn8018692173Median PFS, mo9.4619.2914.8219.12HR (95% CI)0.53 (0.37-0.75)0.78 (0.55-1.11)Estrogen responsivedn8518187178Median PFS, mo9.116.3619.3823.46HR (95% CI)0.53 (0.38-0.74)0.76 (0.52-1.11)RTK genesen8717985180Median PFS, mo12.29NA16.4916.62HR (95% CI)0.55 (0.38-0.79)0.73 (0.51-1.03)CDK4/6 pathwayfn9017682183Median PFS, mo16.5622.0810.8416.49HR (95% CI)0.63 (0.43-0.9)0.67 (0.48-0.94)MAPK pathwaygn9117581184Median PFS, mo12.2922.0812.9117.94HR (95% CI)0.66 (0.47-0.94)0.65 (0.45-0.92)aBreast cancer–related gene; b MKI67, TYMS, MYC, TOP2A; c GATA3, FOXA1, AR, ESR1; d CCND1, PGR, NAT1, FOXA1, RARA, BCL2, BAG1, GATA3, MYC, STC2, XBP1; e AREG, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, FYN, IGF1, KDR, KIT, PDGFA, PDGFRA, PDGFRB, TYRO3; f CCNA2, CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, E2F1, E2F3, TFDP1, CCNB1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN3, RB1, RBBP8, RBL1, RBL2, TP53; g BRAF, HRAS, KRAS, NRAS, RAF1, MAP3K8, NF1. Citation Format: Stephen Chia, Faye Su, Patrick Neven, Seock-Ah Im, Katarina Petrakova, Giulia Val Bianchi, Wei He, Karen Rodriguez-Lorenc, Tetiana Taran, Naveen Babbar, Dennis Slamon. Gene expression analysis and association with treatment response in postmenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer in the MONALEESA-3 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-08.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».